1. Field of the Invention
This invention is directed to purification of novel phosphonate derivatives of glycopeptide antibiotics and related compounds. In particular, this invention is directed to purification of glycopeptide phosphonate derivatives by resin chromatography methods.
2. Background
Glycopeptides (e.g. dalbaheptides) are a well-known class of antibiotics produced by various microorganisms (see Glycopeptide Antibiotics, edited by R. Nagarajan, Marcel Dekker, Inc. New York (1994)). These complex multi-ring peptide compounds are very effective antibacterial agents against a majority of Gram-positive bacteria. Although potent antibacterial agents, the glycopeptides antibiotics are not used in the treatment of bacterial diseases as often as other classes of antibiotics, such as the semi-synthetic penicillins, cephalosporins and lincomycins, due to concerns regarding toxicity.
In recent years, however, bacterial resistance to many of the commonly-used antibiotics has developed (see J. E. Geraci et al., Mayo Clin. Proc. 1983, 58, 88–91; and M. Foldes, J. Antimicrob. Chemother. 1983, 11, 21–26). Since glycopeptide antibiotics are often effective against these resistant strains of bacteria, glycopeptides such as vancomycin have become the drugs of last resort for treating infections caused by these organisms. Recently, however, resistance to vancomycin has appeared in various microorganisms, such as vancomycin-resistant enterococci (VRE), leading to increasing concerns about the ability to effectively treat bacterial infections in the future (see Hospital Infection Control Practices Advisory Committee, Infection Control Hospital Epidemiology, 1995, 17, 364–369; A. P. Johnson et al., Clinical Microbiology Rev., 1990, 3, 280–291; G. M. Eliopoulos, European J. Clinical Microbiol., Infection Disease, 1993, 12, 409–412; and P. Courvalin, Antimicrob. Agents Chemother, 1990, 34, 2291–2296).
A number of derivatives of vancomycin and other glycopeptides are known in the art. For example, see U.S. Pat. Nos. 4,639,433; 4,643,987; 4,497,802; 4,698,327; 5,591,714; 5,840,684; and 5,843,889. Other derivatives are disclosed in EP 0 802 199; EP 0 801 075; EP 0 667 353; WO 97/28812; WO 97/38702; WO 98/52589; WO 98/52592; and in J. Amer. Chem. Soc., 1996, 118, 13107–13108; J. Amer. Chem. Soc., 1997, 119, 12041–12047; and J. Amer. Chem. Soc., 1994, 116, 4573–4590.
The preparation of glycopeptide antibiotics generally includes a purification step. Methods suitable for purifying gylcopeptides, particularly vancomycin and related compounds, are described, for example in U.S. Pat. Nos. 4,440,753, 4,845,194, 4,874,843, 5,149,784, 5,258,495, and 5,853,720. Other methods are disclosed in WO 91/08300 and WO 93/21207.
Despite the above referenced disclosures, a need currently exists for novel glycopeptide derivatives having effective antibacterial activity and an improved mammalian safety profile. In particular, a need exists for glycopeptide derivatives which are effective against a wide spectrum of pathogenic microorganisms, including vancomycin-resistant microorganisms, and which have reduced tissue accumulation and/or nephrotoxicity. Further, in order for these novel derivatives to be useful, there is a need for effective methods of purifying said compounds which recover the product in a highly pure form suitable for pharmaceutical product synthesis.